Substituted thiazolidine-4-ones

ABSTRACT

IN WHICH N IS 0 OR 1, R is a hydrogen atom or a bromine atom, R1 is a hydrogen atom, an alkyl, or alkenyl group which may be substituted by a halogen atom, or a hydroxyl, a carboxylic acid, carboxamide, substituted carboxhydrazide or carboxylic acid ester group or a primary, secondary or tertiary amino group, or R1 is a carbalkoxy group, an alkynyl group, an azomethine group or a cycloalkyl, aryl or aralkyl group, which cycloalkyl, aryl or aralkyl group may be substituted by one or more halogen atoms or hydroxyl, sulphonamido, nitro or carboxylic acid groups, X is an oxygen or sulphur atom or an amino group having the formula IN WHICH R2 is a hydrogen atom or an alkyl, alkenyl, cycloalkyl, aryl, aralkyl or arylsulphonyl group, which groups may be substituted, or a carbamido or amidinomethyl group and each of R3 and R4 is a hydrogen atom, or an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group, which group may be substituted, or R3 and R4 together with the nitrogen atom to which they are attached form a heterocyclic ring. Tests are described in which activity against a large number of gram positive and gram negative bacteria are reported.   Highly active antibacterials are described which are 5substituted thiazolidine-4-ones having one of the formulas

United States Patent Mousseron [5 4] SUBSTITUTED THIAZOLIDINE-l-ONES [72] Inventor: Max J. Mousseron, Montpellier, Herault,

France [73] Assignee: Etabllssements Clin-Byla, Paris, France [22] Filed: June 3, 1968 211' App]. No.: 733,808

Brown et al., J. Am. Chem. Soc. Vol. 73, pages 3257 to 3259 1951).

Chemical Abstracts ll,'Vol. 48, Co]. 3343 to 3344 1954) (abstract of Sanchez et al.).

Chemical Abstracts [I], 6th Collective index, page 10238 s and 1043 s (1964) and Vol.55, page 1594s (1961).

Chemical Abstracts lV, Vol. 55, Col. 5228 to 5229 (1961) (abstract of Turkevich et al.

Chemical Abstracts, Vol. 50, Col. 971 to 972 (1956) (abstract of Sasaki).

Primary Examiner.lohn D. Randolph Attorney-Stevens, Davis, Miller & Mosher [151 3,678,041 51 July 18,1972

[57] ABSTRACT Highly active antibacterials are described which are S-substituted thiazolidine-4-ones having one of the formulas in which n is 0 or 1, R is a hydrogen atom or a bromine atom, R is a hydrogen atom, an alkyl, or alkenyl group which may be substituted by a halogen atom, or a hydroxyl, a carboxylic acid, carboxamide, substituted carboxhydrazide or carboxylic acid ester group or a primary, secondary or tertiary amino group, or R is a carbalkoxy group, an alkynyl group, an azomethine group or a cycloalkyl, aryl or aralkyl group, which cycloalkyl, aryl or aralkyl group may be substituted by one or more halogen atoms or hydroxyl, sulphonamido, nitro or carboxylic acid groups, X is an oxygen or sulphur atom or an amino group having the formula NR in which R is a hydrogen atom or an alkyl, alkenyl, cycloalkyl, aryl, aralkyl or arylsulphonyl group, which groups may be substituted, or a carbamido or amidinomethyl group and each of R and R is a hydrogen atom, or an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group, which group may be substituted, or R and R together with the nitrogen atom to which they are attached form a heterocyclic ring. Tests are described in which activity against a large number of gram positive and gram negative bacteria are reported.

4 Claims, No Drawings SUBSTITUTED THIAZOLIDINEA-ONES OC-N in which n is Oor l, R is a hydrogen atom or a bromine atom, R is a hydrogen atom, an alkyl, or alkenyl group which may be substituted by a halogen atom, or a hydroxyl, a carboxylic acid, carboxamide, substituted carboxhydrazide or carboxylic acid ester group or a primary, secondary or tertiary amino group, or R is a carbalkoxy group, an alkynyl group, an azomethine group or a cycloalkyl, aryl or aralkyl group which cycloalkyl, aryl or aralkyl group may be substituted by one or more halogen atoms or hydroxyl, sulphonamido, nitro or carboxylic acid groups, X is an oxygen or sulphur atom or an imino group having the formula tain a free carboxyl group in which casethey form salts with mineral and organic bases such as the alkali metal bases, am-

monia and amines. On the other hand they may contain prima-' ry, secondary and tertiary amino groups in which case they form salts with mineral and organic acids, especially with pharmaceutically acceptable mineral and organic acids, e.g. the hydrochlorides.

According to a feature of the invention the S-substituted thiazolidine-4-ones having the above general formulas may be produced by a process which comprises reacting a S-nitrofuran aldehyde having the general formula in which n and R are as above defined, with a thiazolidine-4- CHO one having one of the generalformulas O--N-R 0 C-N Ha =X and H2(]J iii-NIUB in which X, R, R and R are as above defined, in the presence of a dehydratingagent.

The S-nitrofuran aldehyde used is 5-nitofurfural, fi-(S- nitrofuryl-2)acrolein or a-bromo-fl-(S-nitrofuryl-Z )-acrolein.

The thiazolidine-4-one employed may or may not have a substituent present in the 3-position. When there is no substituent in the 3-position the condensation product, which corresponds to the following formula:

(Ill) as wellas most of its derivatives corresponding to the general formula in which R is as defined above other than hydrogen, are already known. The remaining derivatives lV may be obtained by condensation of monochloroacetic acid with an alkali metal dithiocarbamate and subsequent closure of the lactam ring by heating in the presence of a strong mineral acid.

Condensation of a rhodanine W with the nitrofuran aldehyde may be carried out in the presence of a dehydrating agent such as anhydrous sodium or potassium acetate in a single diluent (for example methanol, ethanol or acetic acid) or, more' preferably, in a mixture of diluents (for example, a mixture of ethanol and acetic acid). The condensation is carried out by heating the reactants to'between 60 and C for a time which is usually between i and 4 hours. The resulting products generally precipitate; they are isolated after cooling by the usual methods and may be recrystallized from solvents such as nitromethane and dimethylformamide.

If compounds having the general formula III in which R H, n 0 or 1 and X S are treated with formaldehyde or trioxymethylene in solution in dimethylforrnamide and subjected to moderate heating, the corresponding hydroxymethyl derivatives l R Cl-l OH) are obtained in good yields. The presence of a catalyst is not essential although traces of organic bases such as piperidine or morpholine may be added. The bond connecting the hydroxymethyl group to the nuclear nitrogen atom is not very stable and breaks on heating above [20 C, liberating the starting material. By treating compounds Ill (X S) with the stoichiometrical quantities of formaldehyde (or trioxymethylene) and a secondary amine, for example, morpholine in suspension in ethanol or in solution in dimethylfonnamide, the corresponding Mannich base is formed even at room temperature.

Appropriately substituted thiazolidine-4-ones may also be obtained by treating rhodanine N-acetic acid (R CH COOH in formula IV) with thionyl chloride in solution in benzene and then reacting the resulting acid chloride with ammonia or with a secondary amine such as pyrrolidine or morpholine or with a hydrazide such as isonicotinic acid hydrazide.

C=O s (V) In this case, if R is a substituent other than a hydrogen atom, this substituent may have been introduced into the thiazolidine-ZA-dione by means of one ofits alkali metal salts, generally the potassium salt formed by treatment with potash in solution in ethanol at room temperature (the corresponding sodium salt is obtained in analogous manner or by means of sodium hydride). 'Ihis salt is condensed with a halogen compound RHal in which Hal is a halogen atom, preferably bromine or an iodine, in solution either in methanol or in ethanol under reflux or in dimethyl formamide under reflux if these halogens are relatively non-volatile. Derivatives in which R is an alkyl group can be obtained by means of other alkylating agents, such as by the action of diazomethane (if R CH or by reaction with dialkyl-sulphates.

Condensation of the nitrofuran aldehydes is conveniently carried out by heating in solution in acetic acid in the presence of anhydrous sodium or potassium acetate at temperatures in the region of 100 C until no further precipitation of the condensation product takes place. After prolonged cooling, the solid is isolated and recrystallized from a solvent which may be chosen from the following: methanol, ethanol, acetic acid, dioxane and dimethylformamide. The following reaction scheme illustrates the series of reactions enumerated above:

If, in the final product, it is desired that R be other than hydrogen, it is sometimes preferable to condense a thiazolidine-2,4-dione which is unsubstituted in the 3-position with a nitrofuran aldehyde and to convert the product into an alkali metal derivative e.g. by means of an ethanol solution of sodium or potassium hydroxide at room temperature. The derivative thus obtained then reacts rapidly with a compound RHal in which Hal is a halogen in solution in methanol or ethanol under reflux or, even better, in dimethylformamide at about 100 C. After concentration of the solvent under reduced pressure and treatment with water, the products are obtained in very good yields.

Another process for obtaining the same products comprises hydrolyzing the corresponding Z-imino-derivatives containing the substituent R in the 3-position with a strong mineral acid for several hours at about l C according to the following equation:

This method, however, does not always give satisfactory results because a substantial proportion of unreacted starting material may be present in the product.

As in the rhodanine series, the condensation products in which the 3-position is free are capable of yielding Mannieh bases with aliphatic secondary amines such as dimethylamine, diethylamine and diethanolamine or cyclic amines such as pyrrolidine, piperidine, morpholine, piperazine or 4-(5- hydroxyethyl)-piperazine under the same conditions as their homologues. Suitable diluents are ethanol (the reaction taking place in a heterogeneous medium), dioxane or dimethylformamide. Treatment with formaldehyde also leads to the formation of derivatives which are hydroxymethylated in the 3- position, these products having the same instability when heated as the homologous derivatives of rhodanine; in effect, they lose one equivalent of formaldehyde at temperatures from C upwards.

The derivatives of 2-imino-thiazolide-4-one or pseudothiohydantoin (R R H in formula VI) have the same characteristic feature as the homologues which have just been described, namely nucleophilic reactivity of the methylene group in the 5-position, as a result of which they readily undergo the Knoevenagel reaction with the 5-nitrofuran aldehydes.

Compounds of the formula VI above are generally obtained by the condensation of N,N'-disubstituted thioureas with monochloroacetic acid or with its methyl or ethyl ester. If on the other hand, a monosubstituted thiourea is used a mixture of two isomers (Vla and Vlb) may be obtained, and one of these isomers (the Vlb isomer) may in turn be the result of an equilibrium between two tautomeric forms (Vlb and Vlb) as illustrated by the following reaction:

group and R is as hereinbefore comparable quantities of the two isomers Vla and Vlb. If the heating time in the cyclization step is prolonged, the Vla isomer (labile form) may be converted into the stable Vlb isomer which has been isolated in high yields.

The structure of the above products is confirmed by spectrographic studies.

Starting from unsymmetrically disubstituted thioureas, only treating the corresponding pseudothiohydantoin with an arylsulphonyl chloride in pyridine. The semicarbazone of the 2- derivative is obtained by treating the corresponding rhodanine with semicarbazide in known manner while the Z-guanidyl the following type of amine can be formed: derivative may be obtained by ring closure of thioglycollic acid with cyanoguanidine in aqueous solution while heating. OC---N R3 I Condensation of all these derivatives with the mtrofuran alk dehydes may be carried out under the conditions already men- S tioned above, namely heating in an acetic acid medium in the (VIC) presence of anhydrous sodium or potassium acetate until the Compounds of the formula We may be obtained by treating Product has P'Ieclpltated; l h and punfichtioh y be the sodium or potassium salts f the monosubstimted fected as previously described. It IS not essential to isolate the pounds a i h an .alkyla'tin agent or b treating thiazolrd ne-4-one before condensation with the nitrofuran alrhodanine with a Secondary amine (which may be a Secondary l 5 dehyde since these two reactions of forming the he terocycle cyclic amine). All these types of products are obtained by the and condensation of h y take Place simultanering closure of the corresponding thioureas by heating with ywhen the 3'Posltloh f uhsuhstltuted the Products are monochloroacetic acid or with its methyl or ethyl esters in a Capable of uhfiel'golhg certam reactions h as those leading diluent such as ethanol, Z-propanol, n-butanol, acetic acid'or 9 the formation of the correspohd'hg Mahhlch bases y Yeac' benzene. Depending upon whether or not sodium or potassitloh i formaldehyde and asecohdary um acetateis added the cyclization product is obtained either yp Compounds Produced accordmg to the lhfehtloh in the form of the base or in the form of the hydrochloride. are listed the following Tables; the examples to which the The aryl 2-suIphonyIamido-dcrivativcs may be obtained by first column refers follow the Tables! TABLE I O C-1II-R OQN (CH=(|J),.-CH=C /C=S 0 R S 1311- M.P., ample Code n R R degrees Name 1 10290 0 150 3ethyl-5-(5-nltrolurfurylldene)-2-thioxothlazo11dlne-4-one.

10289 0 190 3-methyl-5-(5'-n1tro1ur1urylldene-2-th1oxoth1azo1ldine-4ono. 10291 0 145 3-a11yl-5-(5'-nltrotu.rfurylidene)-2-thloxoth1azolid1ne-4-one. 10292 0 124 3-n-heptyl-5-(fi'mltroturt'urylldene)-2-thioxothlazolidine-4-one. 10293 0 104 3-n-dodecyl-5-(5-nitroturturylldene)-2-thloxothlazolldlne-4-one. 10381 0 114 3-n-hexadecyl-5-(5'-nltroturt'urylldene)-2-thloxothiazolldine-4-one. 10294 0 163 3-hydroxyethy1-5-(5 -n1tro1urturyl1dene)-2-thloxothlazo11dine-4-ono. 10385 0 154 3-cyclopropy1-5-(5-nItroturfurylidene)-2-th1oxothlazolldlne-4-one. 10387 0 203 3-0rtho-hydroxycyclohexyl-5-(5-n1troturturylldene)-2-thioxothiazolid1ne-4-one.

2 10463 1 21350 5-[2'-bromo-2-(5"-nitroturturylldene)ethylldens]2-thioxo-thlazolidlne-4-one.

3 10452 1 235 5l2 -(5-nltroturfury1idene)ethylldene1-2-thloxo-thlazolidlneA-one. 4 10374 0 Cprboxymothyl It) 280 Ammonium salt of 3earboxymethy1-5-(5-nltrotur[urylidene)-2-th1oxo-t1dazo1ld1ne4-one.

ammon um sa 10483 1 II Carboxymethyl 230 3-08rboxymethy1-5-[2-(5-nitroturturylldene)ethylldene]-2-thloxothlazolldine-4-one. 10380 0 l-Carboxyethyl I 180 Ammonium salt 01 3(1' -carboxyethyl)-5-(5-nitrofurlurylidene)-2-thioxo-th1azolidlne-4- (Ammonium salt). one. 10481 0 Curbethoxymethyl 206 3-ethoxycarbonylmethyl-5-(5-nltroturlurylldene)-2-thioxo-thlazo1idine-4-one. 10482 1 11 .do 170 3-ethoxycarbonylmethyl-5-[2-(5-nitroiurlurylidene)ethylldene]-2-thioxothlazo1idlne-4- one.

5.. 10580 0 lyrrogdlnoearbamoyl- 264 3-pyrrolldinocarbamoylmethyl-B-(5-nitroturturylidene)-2-thioxothiazolldlne-4-one.

met. y 10581 1 do 253 a-pgfrolidlnocarbamoylmethy1-5-[2-(5-nitroiurfurylldene)ethylldeneIZ-thloxo-thlazolne-4-0ne. 10578 0 Carbamoylmethyl 265 3-carbamoylmethyl-5-(5'-n1trofurlurylldene)-2-thioxo-thiazolldine-4-one. 10579 1 11 .d0 270 3-carbamoylmethyl-5-[2-(5 -nltroturluryl1dene)-ethylidene]-2-thioxothlszolidinei-one. 10583 0 Morpthfililnocarbamoyl- 188 3-morpholinocarbamoylmethyl-5-(5-nitrofurfurylldene)-2thioxoth1azo1ldine-4-one.

me y 10584 1 do 260 11-13531- 312011noearbamoylmethyl-lS-[W-(H-n1trofurlury1ldene)ethylidene]-2-th1oxo-th1azol- 1 ne -one. 10586 0 N-isonicotlnylhydra- 272 3-N-(isonicotinyl)hydrazidocarboxymethyl-5-(5"-n1tro1urlurylidene)-2-thioxoztdocarboxymethyl. thiazolldlnc-4-one. 10687 1 H N-isonlcotinylhydrazldo- 274 3-(N-lson1eotlnyl)-hydrazidocarboxymetliyl-5-[2"-(5"-nitrolurfurylldene)ethylidene1-2- carboxymethyl. thioxo-thiazolldlno-4-one.

6 10683 1 H Methylol 1 B 192 3-hydroxymethyI-5-[2'-(5-nltrofurturylidene)ethylldens]-2-thioxothiaz01ldine-4-on0. 10082 d0 174 3-hydroxymethyl-5-(5-nltroturturylidene)-2-thloxo-th1azolidine-4-one.

7 10540 0 3-morpholinomethyl. 156- 3-N-mothy]morpholino-5-(5-nitrolurt'urylidene)-2-thioxo thiazolidine-i-one.

8 10535 0 Para-ibdenzenesulphon- 260 3-para-sulphamoylphenyl-5-(5'-nitrofurlury1idene)-2-thioxo-thiazolidine-4-one.

' am 0. 1 536 1 H .....(10 283 3-para-sulphamoylphenyl-JS-[2-(5"-nitroturfurylidene)ethylidenefl-2-thioX0-thial0lldin9- 4-ono. 10382 0 Para-chlorophenyl 202 3-para-chlorophenyl-5-(5-nitroturlurylidene)-2-thiorro-thlazolldine-4-one. 10432 0 Para-carboxyphenyl 268 3-para-carboXyphenyl-5-(5-nitrofurfury11dene)-2-th1oxo-thiazohdine-4-one. 10383 0 Benzyl 215; 3-benzy1-5-(5-n trofurfurylldene)-2-thioxothiazolidine-4-one.

2 6 10384 0 Para-chlorobenzyl 225 3-para-ch1orobenzyl-5-(5-nitrofurlurylidene)-2-thioxo-thiazolidine-4-one. 9 10430 0 5-nirlgloiurfurylidene- 253-8 3-(5-nitrofurlurylideneamino)-6-(5"-nitrot'urturylidene)-2-thioxothiazo1idine-4-one.

a no. I 5

1 Dec. 3 Inst.

(103 85), or 2-hydroxy-cyclohexyl (10387) group are obtained in a similar manner by using the corresponding 3-substituted rhodanines.

EXAMPLE 2 Compound 10453.

One gram (0.004 mol) of a-bromo-B-(S-nitrofuryl-2)- acrolein is dissolved in 5 m1 of ethanol and treated with 0.53 g (0.004 mol) of rhodanine dissolved in 5 ml of hot ethanol and then with 1.32 g of anhydrous potassium acetate dissolved in 6 ml of acetic acid. After heating on a water bath at 60 C for 4 hours, a precipitate is formed which is separated by suction filtration after cooling, washed with water and ethanol and finally recrystallized from nitromethane. The compound is a red powder which melts at 218 to 220 C and weighs 0.7 g (yield: 49 percent).

EXAMPLE 3 Compound 10452.

One gram (0.0075 mol) of rhodanine dissolved in 12 ml of absolute ethanol and 2.2 g of anhydrous potassium acetate dissolved in ml of pure acetic acid are added to 1.26 g (0.0075 mol) of B-(5-nitrofuryl-2)-acrolein dissolved in 8 ml of absolute ethanol.

After heating on a water bath at 75C for 2 hours and cooling, the precipitate is separated by suction filtration, thoroughly washed with alcohol and dried. The product is obtained in the fonn of red needles which turn yellow when washed with a little dimethylfonnamide. 1.52 g is obtained (yield 72 percent). M.p. =235 C.

EXAMPLE 4 Compound 10374.

The following solutions are prepared: 2.82 g (0.02 mol) of S-nitrofurfural in ml of ethanol, 3.82 g (0.02 mol) of N- rhodanine acetic acid in 40 ml of ethanol and 5.5 g of anhydrous potassium acetate dissolved in 35 ml of acetic acid. These solutions are mixed together and heated at 70 C on a water bath for 4 hours; after removal of the major portion of the alcohol under reduced pressure, the precipitate obtained is washed with water, then with alcohol and recrystallized from nitromethane. It melts at 218 C. 4.2 g of product is obtained (yield: 67 percent).

The acid is suspended in a little distilled water and neutralized to pH 7.0 with a 0.1 N ammonia solution. By lyophilization of the solution, the ammonium salt, which melts at 230 C with decomposition, is obtained.

Similar compounds having in the 3-position a carboxymethyl group (10483), l-carboxyethyl (10380) or carbethoxymethyl (10481) as well as the compound having a 2'- (5 "-nitrofurfurylidene) ethylidene group in the 5-position and a carbethoxymethyl group in the 3-position (10482) are obtained in analogous manner to that described above from the correspondingly substituted rhodamine derivatives.

EXAMPLE 5 Compound 10580.

3.84 g (0.02 mol) of 3-carboxymethylrhodanine are suspended in 80 ml of anhydrous benzene and treated on a water bath at 80C with 4.8 g (0.04 mol) of thionyl chloride for about minutes with stirring. After this time dissolution is complete and the benzene and excess of thionyl chloride are evaporated under reduced pressure; the residual oil is the crude carboxylic acid chloride.

This oil is dissolved in 50 ml of anhydrous ether and treated, with cooling, with 2.84 g (0.04 mol) of pyrrolidine in 20 ml of ether. The amide which precipitates is separated by suction filtration and recrystallized from methanol. When dried, it weighs 3.2 g (yield 62%) and melts at 212 C.

1.22 g (0.005 mol) of this amide in solution in 10 ml of acetic acid, and 0.705 g (0.005 mol) of S-nitrofurfural in solution in 5 ml of ethanol are added to 1.5 g of potassium acetate dissolved in 8 ml of acetic acid. After heating for 3 hours on a water bath at 65 C, the precipitate is filtered ofi', washed with ethanol and recrystallized from a little acetic acid. The dry product weighs 1.3 g (yield 62 percent) and melts at 264 C.

The derivatives having in the 3-position, a carbamoylmethyl (10578), a morpholino-carbamoylmethyl 10583) or isonicotinylhydrazido carboxymethyl 10586) group as well as those which have a 2-(5" -nitrofurfurylidene)ethylidene group in the 5-position and in the 3-position a pyrrolidino carbamoyl methyl group (10581 a carbamoylmethyl group (10579), a morpholino carbamoyl methyl group (10584) or an isonicotinyl hydrazidocarboxymethyl group (10587) are obtained in an analogous manner from the acid chloride and ammonia, morpholine or isonicotinic acid hydrazide followed by condensation with 5-nitrofurfural or B-(5-nitrofurfuryl-2) acrolein.

EXAMPLE 6 Compound 10683.

13 g (0.046 mol) of 2-thioxo-5[2-(5-nitrofurfurylidene) ethylidene]-thiazolidine-4-one are dissolved at 70 C in 200 ml of dimethylformamide; 0.5 ml of piperidine followed by 8.6 ml (0.1 mol) of 35 percent aqueous formaldehyde are then added thereto. After 2 minutes on a water bath at 70 C, the clear solution is kept at room temperature for 5 hours, and is then poured onto a mixture of ice and water (about 500 ml) containing 5 ml of 35 percent formaldehyde. The precipitate is filtered, washed with 1 percent aqueous formaldehyde and dried under reduced pressure over phosphorus pentoxide at 50 C to constant weight. It then weighs 13 g percent yield), instantaneous melting point: 192 C. By progressive heating it loses one equivalent of formaldehyde at temperatures of C upwards.

The compound which has a 5'-nitrofurfurylidene group in the 5-position 10682) is obtained in a similar manner from 2- thioxo-S-(S -nitrofurfurylidene) thiazolidine-4-one.

EXAMPLE 7 Compound 10540.

1.28 g (0.005 mol) of 5-(5-nitrofurfurylidene)-2-thioxothiazolidine-4-one are suspended in 30 ml of ethanol, and 0.45 ml (slight excess) of 35 percent aqueous formaldehyde is added dropwise and then, while cooling on an ice bath, 0.44 g of distilled morpholine. After 15 hours stirring at room temperature, the precipitate is filtered by suction and dried. A little more of the same product is obtained by evaporating the ethanol. There is obtained 1.7 g (yield 96 percent), m.p. 15 6-1 57 C.

EXAMPLE 8 Compound 10535.

A solution of 0.705 g (0.005 mol) of S-nitrofurfural in 5 ml of ethanol is added to 1.44 g (0.005 mol) of 3-(parasulphonamidophenyl)-rhodanine in solution in the minimum quantity of boiling acetic acid and 1.4 g of anhydrous potassium acetate in solution in 8 ml of acetic acid. After this reaction mixture has been heated on the boiling water bath for 4 hours, the greater part of the solvent is evaporated under reduced pressure, the precipitate is filtered by suction, washed with a little ethanol and dried. The product weighed 1.4 g (yield 68 percent), m.p. (decomposition) 260 C.

The analogous derivatives having in the 3-position a parachlorophenyl (10382), para-carboxyphenyl (10432), benzyl (10383) or para-chlorobenzyl (10384) group as well as that which has a 2'-(5"-nitrofurfiirylidene)-ethylidene group in the 5-position and a para-sulphamoylphenyl group in the 3- position 10536) can be obtained by this process from the corresponding 3-(substituted phenyl) rhodanines and, in the latter case B-(S-nitrofuryl-Z) acrolein.

A solution of 0.85 g (0.006 mol) of S-nitrofurfural in ml of ethanol is added dropwise to 0.89 g 0.006 mol) of 3-aminorhodanine dissolved in a mixture of 15 ml of ethanol and 0.5 ml

of 2N hydrochloric acid. The reaction mixture is kept on a water bath at 60C for 20 minutes and then, after standing overnight at room temperature, the precipitate is filtered by suction and dried; it weights 1.5 g.

The hydrazone prepared as described above (1.5 g, 0.0055 mol) is dissolved in 20 ml of boiling acetic acid and treatedwith 0.85 g (0.006 mol) of 5 -nitrofurfura1 dissolved in 3 ml of acetic acid and 2.5 g of anhydrous potassium acetate dissolved in 15ml of acetic acid. After 3 hours heating on a water bath at 90C and cooling, the precipitate is isolated and recrystallized from nitromethane. M.p. 256258 C. T he product weighed 1.6 g (overall yield: 68%).

EXAMPLE Compound 10743 and its potassium derivative.

A. 118 g (1.2 mol) of anhydrous potassium acetate and 234 g (2 mol) of thiazolidine-2,4-dione are dissolved at 100 C in the course of minutes in 750 ml of glacial acetic acid. The reaction mixture is then left to cool to 75 C, and 126 g (0.9 mol) of S-nitrofurfural dissolved in 250 ml of acetic acid are then added all at once and the resulting reaction mixture heated at 115 C for 45 minutes. After cooling, the solution is poured onto 4 kg of ice and left overnight at room temperature. The precipitate is filtered by suction, washed with ethanol and dried at 100 C under reduced pressure to con- .stant weight since the product contains 1 mol of solvent of crystallization. The product weighed 165 g (yield 76.5 percent). The m.p. is 225 C.

The same product can also be obtained quantitatively from 5-(5'-nitrofurfurylidene)-pseudothiohydantoin prepared as described in Example 27 (see below) by treating 1 g of this product on a boiling water bath for 4 hours, with stirring, with ml of 6N hydrochloric acid.

B. 12 g (0.05 mol) of 5(5'-nitrofurfurylidene)-thiazolidine- 2,4-dione are suspended in 75 ml of pure ethanol and treated at 0 C with a solution of 2.8 g (0.05 mol) of pure potassium hydroxide in 50 ml of pure ethanol. The reaction mixture is allowed to return to room temperature, and stirring continued for 2 hours. The precipitate of the potassium derivative is filtered by suction, washed with a little ethanol and dried. The product weighed 13.6 g (yield 98 percent). M.p. (decomposition) 290 C.

EXAMPLE 1 1 Compound 10744 and its potassium salt.

A. 234 g (2 mols) of thiazolidine-2,4-dione are added to a solution of 196 g (2 mols) of potassium acetate in 800 ml of acetic acid at 90 C. This temperature is maintained until the product has dissolved; 167 g (1 mol) of B-(5-nitrofuryl-2)- acrolein in solution in 400 ml of acetic acid are then added. The temperature is raised to 120 C and held for 1 hour. Precipitation,which is abundant while still hot, is completed upon cooling. The filtered precipitate is washed with a little acetic acid, then with water and alcohol and finally recrystallized from about 700 ml of dimethylformamide. After prolonged drying in a heated oven at 100 C under reduced pressure it melts at 260 C; 146 g of this product are obtained (yield 55 percent).

B. 106 g (0.4 mol) of the product prepared as described above are suspended in 500 m1 of pure ethanol and treated at 0 C with 22.4 g (0.4 mol) of pure potassium hydroxide in solution in 500 ml of ethanol. After 2 hours stirring at room temperature the precipitate of the potassium salt is separated by suction filtration and dried. 120 g of this product are obtained (yield 99 percent), m.p. (decomposition) 325 C.

J5. EXAMPLE 12 Compound 1 1137.

2.34 g (0.02 mol) of thiazolidine-2,4-dione are dissolved in a solution of acetic acidcontaining 2 g of potassium acetate in 8 m1 of acetic acid at about C. When solution is complete, 2.46 g (0.01 mol) of 2-bromo-3-(5'-nitro-furyl-2')-acrolein in solution in 6 ml of acetic acid are added and the reaction mixture is heated under reflux for one hour. After standing overnight at room temperature, the precipitate is separated by suction filtration, washed with a little dimethylformamide, then with ethanol and dried. The product weighed 1.2 g (yield 35 percent). M .p. 260 C.

EXAMPLE 13 Compound 10933.

A. 3.93 g (0.03 mol) of 3-methyl-thiazolidine-2,4-dione in solution in 4 ml of acetic acid are added to 4.23 g (0.03 mol) of S-nitrofurfural in 4 ml of acetic, acid and 5.9 g (0.06 mol) of anhydrous potassium acetate in 12 ml of acetic acid. The mixture is heated at C for one hour and left overnight. The precipitate thus obtained is removed by suction filtration, washed with acetic acid, water and then ethanol and finally recrystallized from dioxane. 2.33 g (yield 31 percent) of a deep yellow powder melting at 208 C are thus obtained.

B. 1 g (0.036 mol) of the potassium derivative of 5(5- nitrofurfurylidene)-thiazolidine-2,4-dione prepared as described in Example 10 is treated with 0.85 g (0.06 mol) of methyl iodide in 10 ml of dimethylformamide on a water bath until the reagents have gone into solution and the potassium iodide formed has completely precipitated; the dimethylformamide is then evaporated under reduced pressure, the residue treated with water and the water filtered off, and the precipitate is then recrystallized from dioxane. 0.86 g (yield 94 percent) of a yellow product which melts at 21 1 to 212 C is thereby obtained.

C. 2.7 g (0.01 mol) of 2-methylimino-3-methyl-5(5'- nitrofurfurylidene)-thiazolidine-4-one the preparation of which is described in Example 29, are treated with 50 ml of concentrated hydrochloric acid under reflux for 7 hours. The insoluble portion is removed by suction filtration of the hot solution, washed with water and dried. It weighs 0.8 g and melts at 210 C; the acid solution contains unhydrolyzed starting .material in the form of the hydrochloride. The product which melts at 210 C is identical with that obtained as described under A and B.

Analogous products which carry, in the 3-position, an ethyl (11064), B-chloroethyl (11080), isopropyl (11071), allyl (10829), n-hexyl (11076), propynyl (11245), n-pentyl (11246), n-heptyl (11248), n-octyl (11250) or n-hexadecyl (1 1252) group as well as those which carry a 2-(5"-nitrofurfurylidene)ethy1idene group in the 5-position and, in the 3- position, a methyl (10934), ethyl (1 1065 isopropyl (l 1072), allyl (10830), n-hexyl (11077), n-pentyl (11247), n-heptyl (11249), n-octyl (11251) or n-hexadecyl (11253) group are obtained by the same processes using the appropriately substituted thiazolidine-2,4-diones as starting materials with in process B the appropriate alkyl or propynyl iodide and in process C the appropriate 2-meth'ylimino-3-alkyl-5-substituted thiazolidine-4-ones.

EXAMPLE 14 Compound 11078.

1.3 g (0.012 mol) of ethyl chloroformate is added, with cooling on an ice bath, to a suspension of 2.78 g (0.01 mol) of the potassium salt prepared as described in Example 10in 25 ml of dimethylformamide. After one hour in the cold, the solvent is evaporated under reduced pressure at 70 C and the residue is treated with water and recrystallized from ethanol.

The product obtained in this way melts at 123124 C and, after drying, weighs 1.67 g (yield 51 percent).

Compound 10827.

A. 8.4 g (0.06 mol) of S-nitrofurfural are added to a solution of 13.2 g (0.06 mol) of 3-ethoxycarbonylmethylene thiazolidine-2,4-dione in 20 ml of acetic acid, and 15 g of anhydrous potassium acetate in solution in 30 ml of acetic acid are then added at 60 C. After a few minutes heating on a water bath at 90 C, an exothermic reaction ensues and copious precipitation takes place. After prolonged cooling, the mass is treated with water and the solid present separated by suction filtration, washed with ethanol and then recrystallized from 7 ml of dimethylformamide, removed by suction filtration, washed with alcohol and dried under reduced pressure. 8.5 g of product are obtained (yield 43 percent), m.p. 180- 181C.

B. 7 g (0.025 mol) of the potassium salt of (5'-nitrofurfurylidene)-thiazolidine-2,4-dione obtained as described in Example 10 are treated with 6.12 g (0.05 mol) of ethyl chloroacetate in 40 ml of dimethylformamide on a boiling water bath for 1 hour. After removal of the dimethylformamide under reduced pressure and treatment with water, the precipitate obtained is separated by suction filtration, washed with ethanol and recrystallized from acetic acid. 7 g of product (yield 86%) are thereby obtained. M.p. 181-182 C.

EXAMPLE 16 Compound 10828.

This product is obtained by one or other of the two methods described in the preceding Example, substituting fi-(S-nitrofuryl-2)-acrolein for S-nitrofurfural in part A or the potassium salt obtained as described in Example 11 for that of Example 10 in part B. The two samples obtained in this way both melt at 150 C.

EXAMPLE 17 Compound 11067.

2.78 g (0.01 mol) of the potassium salt the preparation of which is described in Example 10, 1 g (0.0105 mol) of monochloroacetic acid and 25 ml of dimethylfonnamide are heated at 90 C for 3 hours. After concentration of the solvent under reduced pressure and treatment with water, the residue is separated by suction filtration and recrystallized from 250 ml of water. 1.5 g (yield 50 percent) of a product which melts at 1 C is thus obtained.

EXAMPLE 18 Compound 1 1079.

The method described in the preceding Example is repeated using the potassium salt obtained in Example 1 1, to give the desired product in 66 percent yield. It melts at 245 C.

EXAMPLE 19 Compound 10946.

6.4 g (0.028 mol) of 3-(3-ethoxycarbonyl-2-propenyl)- thiazolidine-2,4-dione and 4 g of S-nitrofurfural (0.028 mol) in solution in 6 ml of pure acetic acid are treated with 5.5 g (0.056 mol) of potassium acetate in solution in 1 1 ml of acetic acid at 95 C. After 2 hours at room temperature and treatment with water, the precipitate is isolated and recrystallized from acetic acid. It has m.p. 154 C and 2.36 g is obtained (yield 24 percent).

This product can also be obtained by heating the potassium salt described in Example 10 with ethyl 'y-bromo-crotonate.

EXAMPLE Compound 10947.

Replacing S-nitrofurfural used in the preceding Example by molar equivalent of fl-(S-nitrofuryl-Z)-acro1ein, a small yield of the desired product is obtained. The yield is almost quantitative, however, when the potassium salt obtained as 7 ra-m described in Example 11 is heated with ethyl ybromocrotonate dissolved in dimethylfonnamide and proceeding as described in Example 15 B. This product melts at 173C.

EXAMPLE 21 Compound 10787.

18 g (0.075 mol) of 5(5'-nitrofurfurylidene)-thiazolidine- 2,4-dione prepared as described in Example 10 are dissolved in ml of dimethylformamide at 70 C. 0.5 ml of piperidine are added thereto, followed by 13 ml of 37 percent fonnaldehyde (0.15 mol). After two more minutes at 70 C the reaction mixture is allowed to stand at room temperature for 12 hours, the solution poured on 300 ml of a mixture of water and ice containing 10 ml of 37 percent formaldehyde. The precipitate which is obtained is separated by suction filtration, washed with 1 percent aqueous fonnaldehyde, separated by suction filtration and dried in the presence of phosphorus pentoxide under reduced pressure at C. The dry product weighs 15 g (yield 74 percent). When heated at progressively increasing temperatures, it loses one equivalent of fonnaldehyde from C upwards to yield the starting material.

EXAMPLE 22 Compound 10932.

0.86 ml (0.01 mol) of 35 percent formaldehyde are added at 80 C to 1.33 g (0.005 mol) of 5[2'-(5-nitrofurfurylidene) ethylidene]-thiazolidine-2,4 dione in solution in 12 ml of dimethylformamide. After 10 minutes at 75 C, the solution is left to stand overnight at room temperature and then treated with three volumes of a mixture of ice and water; the solid formed is separated by suction filtration, washed with a little 1 percent aqueous formaldehyde and then dried under reduced pressure in the presence of phosphorus pentoxide.

The product obtained in this way weighs 1 g (yield 68 percent). lt loses fonnaldehyde when heated above 120 C.

EXAMPLE 23 Compound 10985 1.33 g (0.005 mol) of 5[2'-(5"-nitrofurfurylidene) ethylidene]-thiaz0lidine-2,4-dione in suspension in 25 ml of ethanol is treated with 0.45 ml (slight excess) of formaldehyde in a 35 percent aqueous solution and with 0.055 mol of 15 percent ethanolic dimethylamine. After stirring for one hour at room temperature, the precipitate is separated by suction filtration, washed with a little ethanol and dried at 100 C under reduced pressure. It weighs 1.2 g and melts at C.

Operating in a similar manner in dioxane or in dimethyl formamide as solvents, the analogous compounds which carry, in the 3-position, a diethylaminomethyl (11136), bis(B-hydroxyethyl)-aminomethyl (1 1003), pyrrolidinomethyl (11000), piperidinomethyl (1 1004), morpholinomethyl (10889), piperazino methyl (11075) or 4-(fi-hydroxyethyl)- piperazinomethyl (11066) group as well as those which carry a 5'-nitrofurfurylidene group in the 5-position and, in the 3- position, a dimethylamino methyl (11001 bis-(fi-hydroxyethyl)-aminomethyl (10988), pyrrolidinomethyl (10999), piperidinomethyl 10989) or morpholinomethyl (10888) group are obtained from the two starting compounds prepared as described in Examples 10 and 11 and substituting the appropriate secondary amines for dimethylamine.

EXAMPLE 24 Compound 10677.

9.8 g (0.05 mol) of the hydrochloride of 3-(B-aminoethyl)- thiazolidine-2,4-dione in solution in 50 ml of acetic anhydride are heated at 140C for 3 hours; the solvent is then evaporated under reduced pressure and the acetyl derivative obtained is recrystallized from water. 6.35 g are obtained. M.p. 1 16 C.

2.02 g (0.01 mol) of this derivative and 1.41 g (0.01 mol) of S-nitrofurfural in solution in 10 ml of pure ethanola are treated with 2.94 g (0.03 mol) of potassium acetate in solution in 10 ml of pure acetic acid and the whole is heated to boiling on a water bath for 4 hours. The solid which has precipitated is filtered after the reaction mixture has been allowed to cool and is recrystallized from ethanol. It is a yellow product which melts at 182 C and weighs 0.9 g.

0.8 g of this condensation product and 20 ml of 4N- hydrochloric acid are heated under reflux for 4 hours. After one night in the refrigerator, the hydrochloride is separated by suction filtration, washed with a little ice water and dried. It weighs-0.6 g. The instantaneous melting point is 205 C.

EXAMPLE 25 Compound 10741 This product is obtained from the hydrochloride of S-(B- aminoethyl)-thiazolidine-2,4-dione and B-(S-nitrOfuryl-Z) acrolein by the process described in Example 24. It is soluble in cold water to the extent of 4 g per liter. The instantaneous melting point is 220 C.

EXAMPLE 26 Compound 10831.

5.56 g (0.02 mol) of the potassium salt of 5(5'-nitrofurfurylidene)-thiazolidine-2,4-dione the preparation of which is described in Example 10, and 3.16 g (0.025 mol) of benzyl chloride in 50 ml of dimethylformamide are heated on a boiling water bath for 3 hours. After evaporation of the solvent under reduced pressure and treatment with water, the residue is removed by suction filtration and recrystallized from acetic acid. Five grams (yield 76 percent) of the product which melts at 201 C are thus obtained.

A similar compound which carries a para-nitrobenzyl group in the 3-position (10833) (from para-nitrobenzyl chloride) and those which carry a 2-(5"-nitrofurfurylidene) ethylidene group in the 5-position and, in the S-positiori, a benzyl group (10832) or a para-nitrobenzyl group (10834) are obtained in the same manner from the potassium salts described in Examplesand11.

EXAMPLE 27 Compound 10746.

1.67 g (0.01 mol) of B-(5-nitrofuryl-2)-acrolein in solution in 5 ml of acetic acid is added to a solution of 2.44 g (0.025 mol) of anhydrous potassium acetate and 1.16 g (0.01 mol) of pseudothiohydantoin in 10 ml of acetic acid at 70 C. The whole reaction mixture is kept on a water bath at this temperature for 6 hours. After prolonged cooling, the precipitate is separated by suction filtration, washed with acetic acid, then with water and lastly with ethanol and dried; the dark brown solid product thus obtained weighs 1.52 g (yield 57 percent): it is recrystallized from dimethylformamide. In the pure state, it is an orange yellow solid which melts with decomposition at about 300 C.

EXAMPLE 28 Compound 11141.

Two grams of anhydrous potassium acetate are dissolved in 8 ml of pure acetic acid; 1.3 g (0.01 mol) of 3-methyl-2-iminothiazolidine-4-one is then dissolved therein and then, after the addition of 1.41 g (0.01 mol) of 5-nitrofurfural in solution in 2 ml of acetic acid, this solution is heated on a water bath at 60 C for minutes. After cooling, the solid formed is removed by suction filtration, washed with a little acetic acid, then water and lastly with ethanol and dried. It can be recrystallized from dimethylformamide. 2.45 g (yield 97 percent) of the product is obtained, m.p. 259260 C.

Compound 1 1142 which melts at 224-225 C is obtained by replacing S-nitrofurfural by a molar equivalent of B-(S- nitrofuryl-2)-acrolein in the above example.

' EXAMPLE 29 Compound 1 1025.

A solution of 1.41 g (0.01 mol) of S-nitrofurfural, 1.44 g (0.01 mol) of 2-methylimino-3-methyl thiazolidine-4-one and 1.9 g (0.02 mol) of anhydrous potassium acetate in 9 ml of acetic acid is heated out 60C for 7 minutes. The orange yellow precipitate which forms is separated by suction filtration after complete cooling, and washed with water and ethanol. (22.08 g (yield: percent) are thereby obtained. M.p. 238

This product may be recrystallized from dimethylformamide; the product obtained is greenish yellow. M.p. 240 C.

Analogous compounds which have an allyl group in the 3- position and an allylimino group in the 2-position 10983) or a phenyl group in the 3-position and a phenylimino group in the 2-position (10986) as well as those which have a 2'-(5"- nitrofurfurylidene)ethylidene group in the 5-position and, in the 3-position and 2-position, methyl and methylamino groups respectively (11026), or ally] and allylimino groups respectively, (10984) are obtained under similar conditions but with longer time of heating starting with the correspondingly substituted thiazolidine-4-ones and in the two latter cases, B-(S- nitrofuryl-2)-acrolein.

EXAMPLE 30 Compound 11002.

1.96 g (0.02 mol) of anhydrous potassium acetate dissolved in 4 ml of acetic acid, and then 1.41 g (0.01 mol) of 5-nitrofurfural in solution in 3 ml of acetic acid, are added to 1.92 g (0.01 mol) of 2-phenylimino-thiazolidine-4-one in solution in 3 ml of acetic acid. The solution is heated on a water bath at 75 C for 2 hours 30 minutes. After cooling to room temperature, the solid which separates is isolated by suction filtration, washed with water and then with alcohol, and recrystallized from dimethylformamide. When dried the product weighs 1.3 g (yield 41 percent) and melts at 315 C.

The corresponding compound carrying an orthochlorophenylimino group in the 2-position (11005) (using 2- (orthochlorophenylimino-thiazolidine-4-one) or that which has a 2-(5"-nitrofurfurylidene) ethylidene group in the 5- position and a phenylimino group in the 2-position (11019) (usifig B-(S-nitrofuryl-Z) acrolein) is obtained by the same met od.

EXAMPLE 31 Compound 1 1022.

0.5 ml of 35 percent formaldehyde (slight excess) and 0.44 g (0.005 mol) of distilled morpholine are added successively to 1.57 g (0.005 mol) of 2-phenylimino-5(5'-nitrofurfurylidene) thiazolidine-4-one (the preparation of which is described in Example 30) in suspension in 10 ml of dimethylformamide.

Substantially complete solution is effected by heating for one-half hour on a water bath at C, and is followed by copious precipitation. After standing overnight at room temperature, the solid which forms is separated by suction filtration, washed with alcohol and then dried at C under reduced pressure. It weighs 1.8 g (yield 87%) and has an in- 4 stantaneous melting point of 225C.

EXAMPLE 32 Compound 1 8.

1.19 g (0.005 mol) of 2-(para-toluene-sulphonylimino)- thiazolidine-4-one, 0.705 g (0.005 mol) of S-nitrofurfural and 0.98 g (0.01 mol) of potassium acetate are dissolved in 6 ml of acetic acid and heated on a water bath at 60C for 20 minutes. After cooling, the product is separated by suction filtration, washed with acetic acid, water and then ethanol and dried. It weighs 1.3 g (yield: 66 percent) and melts at 267 C.

The corresponding compound carrying a benzene sulphonyl imino group in the 2-position (11060) (starting from 2- benzene-sulphonylimino)-thiazolidine-4-one) and the compounds which carry a 2'-(5"-nitrofurfury1idene)ethylidene group in the -position and, in the 2-position, a para-toluenesulphonylimino group (11059 or a benzene-sulphonylimino group (11061) can be obtained in the same manner starting from B-(5-nitrofuryl-2)-acrolein and the stated thiazolidine-4- ones.

EXAMPLE 33 Compound 1 1073.

0.87 g (0.005 mol) of the semicarbazone of thiazolidine- 2,4-dione in suspension in a solution of ml of acetic acid containing 1 g of potassium acetate is treated with 0.84 g (0.005 mol) of B-(5-nitrofury1-2)-acro1ein for 30 minutes under reflux and with stirring. After the precipitate which forms has been cooled, it is filtered, washed with acetic acid and with ethanol and dried under reduced pressure. This product melts at 248 C.

EXAMPLE 34 Compound 1 1074.

3.28 g (0.02 mol) of 2-guanidinyl thiazolidine-4-one, 2.82 g (0.02 mol) of 5-nitrofurfural and 3.92 g (0.04 mol) of anhydrous potassium acetate are dissolved in 60 ml of pure acetic acid. A precipitate is formed after heating on a water bath at 65 C for 1 hour. It is separated by suction filtration after cooling the reaction mixture, washed with ethanol and then dried. 4.18 g (yield: 71%) of the product is obtained which melts at 366 C.

EXAMPLE 35 Compound 11139.

Four grams of anhydrous potassium acetate are dissolved in 16 ml of acetic acid and 2.6 g (0.02 01) of 2- methylaminothiazoline-4-one and 2.84 g (0.02 mol) of 5- nitrofurfural are added thereto. The solution obtained is heated for 2 hours at 80 C on a water bath. After cooling a solid which separates is isolated by filtration and recrystallized from a small amount of dimethylformamide; it weighs 1.2 g and melts at 328 C.

The products which carry, in the 2-position, an ethylamino group (11062), allylamino (11171), n-propylamino (11143), isopropylamino (11 173), n-butylamino (l 1175) or cyclohexylamino (11177) are obtained by replacing the 2- methylamino thiazolidine-4-one by the appropriate 2-alkylarnino, 2-cyc1oalky1amino or 2-alkeny1amino derivative, and compounds 11140 (2-methylamino), 11063 (2- ethylamino), 11172 (2-ally1amino), 11144 (2-npropylamino), 11174 (2-isopropy1amino), 11176 (2-n-butylamino) and 11178 (2-cyc1ohexylamino) are obtained by replacing S-nitrofurfural by B-(S-nitrofuryl-Z)-acrolein in the above described process. Starting from 2-methylamino-, 2- ethylamino-, 2-isopropy1aminoand 2-cyclohexylaminothiazoline-4-ones and a-bromo-B-(5-nitrofuryl-2)- acrolein, the compounds 11376, 11138, 11377 and 11378, respectively, are obtained.

EXAMPLE 36 sium acetate are successively dissolved by heating in 5 ml of .29. acetic acid and heating is continued at 65 C for 2 hours on a water bath. After prolonged heating and treatment with water, the precipitate is removed by suction filtration, washed with ethanol and recrystallized from a small amount of dimethylgnmamide. It weighs 1 g (yield: 39 percent) and melts at 254 By following the above described process, the corresponding compounds which have a para-chlorobenzylamino (11254), dimethylamino (11262), diethylamino (11273, 1 1390 and 1 1391 methylbenzylamino (1 1274), methylphenylamino (1 1276) or morpholino (11292) group in the 2-position may be obtained using as starting materials the correspondingly 2-substituted thiazoline-4-ones. Those which have a 2-(5"-nitrofurfurylidene)ethylidene group in the 5- position and, in the 2-position, a benzylamino l 1021), parachloro-benzylamino (l 1255), diethylamino (l 1263 and 11389), methylbenzylamino (1 1275), methylphenylamino (11291) or morpholino (11293) group are similarly obtained from fl-(S-nitrofuryl-Z) acrolein and the corresponding 2-substituted amino-thiazoline-4-ones. The homologous compound 1 1379) is obtained from a-bromo-B-(5-nitrofuryl-2)-acrolein and 2-benzylamino-thiazoline-4-one.

The compounds prepared according to the examples were subjected to biological tests, the results of which will now be described.

1. Antibacterial action in vitro.

The technique employed in the study of the products is the inhibition of growth by serial dilutions in Petri dishes containing agar medium.

Into each Petri dish are introduced 2 ml of the intermediate range of products and 18 ml of molten agar, and the dish is heated to 50 C. When the agar has set, the surface is dried at 37 C. The cultures, of 21 strains of bacteria and of 44 strains cultivated for 18 hours in ordinary broth are diluted to H in distilled water and used for inoculation. The dishes after turning upside down are warmed to 37 C in a heating cupboard for 24 hours and the readings are then taken.

2. Action against Koch bacillus in vitro.

The liquid medium used for the tests on the serum was Youmans medium which was placed in tubes measuring 22 mm, in portions of 5 ml per tube. The substance to be tested is distributed among the tubes in such a way that the concentrations range from 10 mcg to 0.05 mg per ml. The medium is inoculated with the Mycobacterium tuberculosis 1-1 37 R V strain from a culture 7 to 9 days old on Dubos medium, carrying out two inoculations (0.01 mg of bacilli and 0.1 mg per 5 ml of medium).

The culture is titrated by nephelometry, comparing the culture in Dubos medium with that of a range covering a series of suspensions of B.C.G..

Readings are taken on the sixth, twelfth and eighteenth day. The bacteriostatic concentration is taken as that concentration which prevents the appearance of a culture which is visible to the naked eye on the sixth day after inoculation with 0.01 mg.

The reading taken on the eighteenth day, especially that with the 0.1 mg inoculation, enables one to have an approximate estimate of the number of resistant bacilli present in a normal strain.

3. Antifungal activity in vitro.

Study of the antifungal properties of the products of the present invention was carried out by inoculation with different fungi and yeasts of a Sabouraud medium containing dilutions of the products ranging from 0.5 to 30 mcg per ml of solidified medium. The reading was taken after the specimen had been in a heating cupboard at 27 C for 5 days.

4. Antiparasiticidal action in vivo.

a. Hymenolepis nana var. Fratema.

Eight weeks old mice were given 100 eggs by the oral route. Four weeks later, the animals were treated with the test material for 3 days. Twentyfour hours after the last treatment, the mice were sacrificed and the percentage of deparasitization noted.

b. Syphacia obvelata.

Four weeks old mice were left in contact with strongly parasitized mice for 8 days. The animals were then treated with the test material by the oral route for 4 days.

Fortyeight hours after the last treatment, the mice were sacrificed and the percentage of deparasitization noted.

c. Nippostrongylus muris.

Three to four weeks old rats were given 200 larvae of Nippostrongylus subcutaneously. On the th, llth and 12th day after inoculation, the animals were treated orally.

On the fourteenth day after inoculation, they were sacrificed and the number of adult parasites counted. The follow ing formula gives the percentage of deparasitization:

N n T 9".

. N and n being the mean number of worms foundin the control animals and the treated animals, respectively. 5. Urinary excretion of the products in the rat.

The method of Hartley, modified by Chabbert (1957) was used for biological dosage. It consists in horizontal diffusion from discs impregnated with urine on an agar medium inoculated with the tests bacteria.

The percentage of excretion is calculated from the reading of the zone of inhibition of growth of the bacteria in relation to a range of the product. Graphs are drawn up in which the concentrations are entered as abscissae and the diameters of the range as ordinates. The activity of the sample to be studied is read directly from the graph obtained in this way. The

specimens of urine were taken 1, 2, 4, 6, 8 and 24 hours after a single dose of the product.

6. Intestinal antiseptic action in the healthy rat.

The excrements of control animals and of animals treated with the test compounds are mixed with distilled water to a known volume by stirring.

From this solution, which is considered the parent solution, dilutions of between 10' and l0" are prepared. 1 milliliter of each dilution is filtered through a millipore filter of 0.45 4. and the filter is placed on an agar medium. After 24 hours at 37 C, the number of colonies per filter are counted. The excrements are taken for analysis 24 hours before the first treatment, 24 hours after treatment, at the third treatment, at the seventh treatment and 3 days after the treatment.

The number of colonies in each dilution after administration of the product to be examined is expressed as a percentage of the corresponding number before administration.

7. Intestinal antiseptic action in the rat infected with Salmonella typhimurium.

The procedure is the same as that described above but the animals are orally 1 ml of an l8-hour culture of Salmonella typhimurium mixed with 1 ml of egg yoke.

The filters are placed on a special Salmonella Shigella (S.S.) medium. Dilutions of the excrements are 10", 5 X 10' and 0 above are shown in the following Tables, numbered 1 to 8.

TABLE 1.AN'IIBACTE RIAL ACTION IN VITRO Minimum inhibiting concentrations in meg. lml.

10137 10933 10934 11064 11080 11065 Staphylococcus londonii.- $0. 05 50. 05 1. 56 0. 4 0. 8 0. 4 0. 8 0. 8 Staphylococcus aureus 521 I 0. 2 0. 2 1. 56 1. 56 12. 5 Streptococcus pyopeues gr. A 561 I 3. 12 1. 56 50 3. 12 Streptococcus a a actiae gr. B 55, 118 3. 12 25 50 25 3. 12 50 Streptococcus faecalla gr. D A 23 3. 12 1. 56 1. 56 12. 5 6, 25 50 Sarcma lutea ATCC 9,341 1. 56 3. 12 6. 25 50 12. 5 12. 5 Bacillus cereus ATCC 9,634- 1. 66 0. 4 3. 12 1. 56 1. 56 1. 56 1. 56 Bacillus suhtilix .A'ICC 6,633 0. 4 0. 8 0. 8 0. s 6, 25 Ltoterla m 5, 1. 56 1. 56 6. 25 12. 5 12. 5 6. 25 25 Coryuebacterium abbott 12. 5 12. 5 50 Past. septica Type 0 5,621 0. 1 0. 4 0. 1 1. 56 1. 56 25 Past. pseudotuberculosic C 114-.. 0.4 3.12 3.12 1.56 25 12.5 50 Each. coli A. 223 IP 3- 12 6. 25 12. 5 3. 12 25 25 50 Each. coli F 250 0. 1 1. 56 50 50 50 Each. colt monod D 198 1.56 0.8 5. 25 1. 56 25 25 50 Klcbaiella pueumoutaeATCO 10,031 3.12 6. 25 6. 25 0. 4 1. 56 31. 2 0. 8 Klcbclclla mistral E 156 50 50 50 Salmonella tuphimurium A 222 IP 6. 25 6. 25 50 6. 25 50 50 50 Salmonella para 13 E 118 3.12 3. 12 50 50 50 Shigella dueeuteriae 5,728 IP 1. 56 3.12 6. 25 1. 56 25 12. 5 50 Pseudomonas aeruginosa A 22 IP 50 50 50 25 50 50 50 TABLE 1.--ANTIBACTE RIAL ACTION IN VI'IRO-Contiuued staphylococcus londom'i 0. 2 3. 12 0. 2 $0. 05 0. 2 0. 1 Staphylococcus aureus 521 IP 0.8 25 0. 4 0. 4 Streptococcus pyogeues gr. A 561 11 6. 25 0. 2 12. 5 Streptococcus agalactiae gr. B 55,118 I}? 6. 25 0. 2 12.5 Streptococcus faecalis gr. DA 28 6. 25 0.8 6. 25 Sarcina lutea ATCC 9,341-... 12.5 0. 8 50 Bacillus cereus ATCC 9,634.; 0. 8 0.4 0. 4 Bacillus subtills ATCC 6,633. 0. 2 0. 2 0. 1 Listeria 'monocytogenes 5,734. 3. 12 0.8 3. 12 Corynebacterium abbott- 25 0. 4 50 Past. septica Type 0 5,621 1. 56 50 0. 8 Past. paeudotuberculosis C 114. 12.5 50 12.5 Each. coli A 223 IP 50 50 1. 56 Each. coli F 260 50 50 3.12 Each. colt monod D 108- 25 50 3. 12 Klebsiella pneumoniae ATCC.10,03 6. 25 50 12.5 'Klebsiella mistral E 156 Salmonella typhimurium A 222 IP. 50 50 12.5 Salmonella para BE 118 50 50 12.5 Shigella dysenteriae 5,728 1P- 12. 5 50 25 Pseudo'monas aerugi-nosa A 22 IP 50 50 50 TABLE 1.ANTIBACTERIAL ACTION IN VIIRO-Continued 10828 11067 11079 10946 10947 10787 10932 10985 Staphylococous londonii 4 2 $0. 0. 1 50, 05 50, 05 Staphylococcus aurcus 521 11 0. 8 0. 4 0. 4 0, 2 Streptococcus puogenes gr. A 501 IP 6. 25 0. 8 3.12 1, 5 1, 5 Streptococcus agalactiae gr. B 55, 8 P 6- 6 1. 56 3. 12 1, 56 1, 5 Streptococcus faecalis gr. DA 23 1 5 0. 8 0.2 1, 56 1 55 Sarcina lutea ATCC 9,341 50 12.5 3.12 12. 5 5, 25 Bacillus cereus ATCC 9,634 3. 12 6. 25 0. 05 1. 56 0. 2 50. 05 Bacillus subtilus ATCO 6,633.. 0.8 50. 05 0. 1 1, 5 5(105 Listeria monocytogenes 5,734.. 3. 12 0.4 1. 56 0.8 0. 4 Corynebacterium abbott..... 25 12.5 25 Past. septica Type C 5,621... 1. 56 0. 2 0. 1 50. 05 0. 4 Past. pseudotuberculosis C 114. 25 1.56 1.56 3.12 1. 5a Esch. coli A 223 IP 6. 25 0. 4 50 50 3.12 0.8 0.8 Esch. coli F 260 .3 3. 12 1. 56 Each. coli monod D 198 6. 5 0. 8 3. 12 0. 8 0. 8 Iflebsiclla pneumoniae ATCC 10 031. 12.5 1.56 50 50 3. 12 6. 1. 56 Klebsiella mistral E 156 3- 12 6. 25 Salmonella lyphz'murium A 22211 50 25 1.56 50 50 6 25 1. 56 3. 12 Salmonella para BE 118.. .5 1.56 3.12 6. 25 3.12 Shigclla dysenleriae 5,728 I 50 6. 25 1. 56 50 50 1 56 0.4 3. 12 Pseudomonas aerugiuosa A 22 I1 50 50 50 50 50 TABLE 1.-ANTIBACTE RIAL ACTION IN VIIRO-Contlnued 11001 11136 10988 11003 10999 11000 10989 11004 Staphylococcus londonii 1 50- 05 0- 1 $0. 05 0. 4 50. 05 0. 2 50. 05 Staphylococcus aurcus 521 IP. 0. 4 0. 2 0. 8 0. 2 0. 8 0. 2 0. 8 0. 2 Streptococcus pyoaenes gr. A 561 IP.. 3.12 1. 56 3.12 1. 56 6. 25 3. 12 6. 25 3.12 Streptococcus agalactiae gr. B 55,118 11. 3.12 1.56 3.12 1. 56 6.25 1. 56 6. 25 3. 12 Streptococcus faccalis gr. DA 23.. 3.12 1. 56 3.12 1.56 12. 5 1. 56 12. 5 1. 56 Sarci'na lutea ATCO 9,341... 50 12. 5 25 25 50 50 50 50 Bacillus ccreus ATCC 9,634. 0. 4 $0. 05 0. 2 0. 2 0. 8 0. 1 3. 12 0. 1 Bacillus subtllis ATCC 6,63 0. 1 $0. 05 0. 4 0. 05 0. 4 50. 05 0. 2 $0. 05 Listeria monocytoaenes 5,734 0. 8 0. 4 1. 56 0. 4 3. 12 0. 4 1. 56 0. 4 Caryncbactcrium abbott... 50 3.12 50 50 50 50 50 50 Past. septlca Type C 5,62 1. 56 0.2 0. 4 0.8 3. 12 0. 8 1. 56 1. 56 Past. pseudotuberculosis O 1 1. 56 3. 12 1. 56 3.12 6. 25 3.12 3. 12 0. 8 Each. coli A 223 IP 1. 56 1. 56 1. 56 0. 4 6. 25 0. 8 3. 12 1. 56 Esch. colt F 260-- 1. 56 1. 56 3. 12 0. 8 6. 25 0. 8 6. 25 0. 8 Esch. Cali monod 1. 56 0. 8 3. 12 0. 8 6. 25 0. 8 6. 25 1. 56 Klebaiella pneumoniae AT 3.12 l. 56 3.12 1. 56 12. 5 0.8 6. 25 1. 56 K lcbsiella 'mistral E 156 25 6. 25 25 12. 5 50 6. 25 50 12. 5 Salmonella tyhimurium A 222 IP.. 3.12 3.12 6. 25 3.12 12. 5 1. 56 12.5 3. 12 Salmonella para BE 118 3.12 1. 56 3.12 1. 56 6. 25 1. 56 6. 25 3.12 Shiyclla dysenteriac 5,728 I1. 1. 56 0. 8 1. 56 1. 56 3.12 1. 56 3. 12 3. 12 Pseudomonas acruginosa A 22 IP 50 50 50 50 50 50 50 50 TABLE 1.--ANTIBACIERIAL ACTION IN VIIROCont1nued 10888 10889 11075 11066 10746 11141 11142 11025 Staphylococcus londonii 0. 1 0. 05 0. 05 $0. 05 0. 05 0. 4 0. 1 0, 2 Staphylococcus aureaus 521 IP 0.2 0. 2 0. 2 0. 1 0.4 0. 8 0. 4 0. 3 Streptococcus pyoqenes gr. A 561 IP 1. 56 0.4 1. 56 0. 8 6. 25 50 0. 8 25 Streptococcus aqalactiae gr. B 55, 118 IP 1.56 0.8 1. 56 0. 8 6. 25 50 0. 8 25 Streptococcusfaecalis gr. DA 23 1. 56 0.8 1.56 0.8 12.5 50 3.12 25 Sarcina lutea ATCC 9,341 6. 25 6. 25 25 12.5 3. 12 25 12. 5 25 Bacillus cereus ATCC 9,634... 1. 56 0.4 0. 1 0. 05 0. 8 3. l2 0. 1 1. 56 Bacillus subtilis ATCC 6,633 0. 1 go. 05 go. 05 go. 05 0. 8 0. 2 go. 05 0. 4 Listeria monocytoqenes 5,734. 0.4 0.4 0.8 0. 4 1. 56 12. 5 0. 8 1. 56 Corynebacterium abbolt 5 6. 5 12.5 12.5 6. 25 12. 5 12. 5 Past. seplica Typo 0 5,621.... 0. 05 $0. 05 0. 4 0. 4 0. 1 0. 8 0. 8 1. 56 Past. pseudotuberculosis C 114. 6. 25 3.12 1.56 12.5 0.8 0. 8 0. 2 1.56 Each. coli A 223 IP 3.12 1. 56 0. 8 0. 8 0. 8 3.12 0. 4 12.5 Esch. coli F 260 1. 56 1. 56 0.8 3. 12 1. 56 3. 12 3. 12 12.5 Esch. coli monod D 198 5 0. 8 0. 8 0. 8 1. 56 3.12 0. 8 6, 25 Klebsiella pneumoniae ATCO 10,031 3. 12 1. 56 1. 56 1. 56 0. 2 0. 2 go. 05 0. 1 Klebsiella mistral E 156 56 66 6. 25 12. 5 8 25 Salmonella typhimurium A 222 IP 3. 12 3. 12 1. 56 3. 12 1. 56 3. 12 3. 12 25 Salmonella para BE 118 1.56 1. 56 1.56 3.12 1.56 6. 25 1.56 25 Shigella dysenteriae 5,728 IP- 1. 56 0.4 3.12 3. 12 0.4 0. 8 0. 2 3. 12 Pseudomonas aeruyinosa A 22 IP 0 50 50 50 50 50 50 50 TABLE 1.-ANTIBACTERIAL ACTION IN VITRO-Continued 11026 10983 10984 10986 11002 11019 11005 11022 Staphylococcus londom'i $0. 05 0. 8 1. 56 1. 56 0.2 $0. 05 0.2 0.2 Staphylococcus aureus 521 II..- 0. 4 3. 12 6. 25 50 3. 12 1. 56 0.2 0.8 Streptococcus pyo enes gr. A 561 IP.- 0.8 50 50 50 50 50 50 50 Streptococcus aga actiae gr. B 55,118 II.. 0.8 50 50 50 50 5O 50 50 Streptococcus faecalz's gr. DA 23 0.8 50 12.5 50 50 25 6. 25 50 Sarclna lutea ATCC 34 50 25 25 50 50 50 12. 5 50 Bacillus cereus A'ICC 9,634. 0. 1 3. 12 0.8 50 50 0.8 0. 8 3. 12 Bacillus subtilis ATCC 6,633.. 0. 1 3. 12 0.8 1. 56 0.4 0.8 0. 2 1. 56 Listeria monocytogencs 5,734.... 0. 4 6. 25 3. 12 50 25 0. 8 0. 8 25 Corynebacterium abbott 50 50 50 50 50 50 50 50 Past. septica Type 0 5,621 0.8 25 25 50 50 50 3. 12 50 Past. pseudotuberculosis C 114 0.4 50 50 50 50 50 12.5 50 Each. cell A 223 IP 1. 56 50 50 50 50 50 25 50 Esch. coli F 260 50 50 50 50 50 50 50 Each. cola monod D 198 0.8 50 50 50 50 50 50 50 Klebsiella pneumoniae A'ICC 10,031. 50 12.5 50 50 50 50 50 50 Klebsiella mistral E 156 50 50 50 50 50 50 50 50 Salmonella typhimurium A 222 IP. 50 50 50 50 50 50 50 50 Salmonella para BE 118 50 50 50 50 50 50 50 50 Shigella dysentcriae 5,728 IP- 1. 56 50 50 25 50 50 12. 5 50 Pseudomonas aeruginosa A 22 1 50 50 50 50 50 50 50 50 -Cont1nued TABLE 1.--AN'IIBACTERIAL ACTION IN VITRO TABLE l.-ANTIBACTERIAL ACTION IN ylTRp-Continued Staphylococcus lomionii $0. 0. 05 0. 1 50. 05 go. 05 Staphylococcus 209 II 0.4 0. 4 0. 4 0. 2 0,4 Straphylococcus aureus Gervais D 319 0.4 0.4 0.4 0. 2 0.4 Straphylococuss aureus E 120 0. 2 0. 2 0.4 0. 2 0. 2 Straphylococcus albus P 0 1,200... 0. 1 0.1 1. 56 0. 8 0. 2 Streptococcus pyogenes gr A 561 IP.. 1. 56 1. 56 1. 56 0. 4 0. 2 Streptococcus pyogenes gr A D 313 0. 4 0.4 4 0. 1 0. 2 Streptococcus agalactiae 31 B.. 3.12 1. 56 1. 56 0.8 1. 56 Streptococcus pyogenes gr C... 0.8 0. 8 1. 56 0. 8 0. 4 Streptococcus [aecalis "81". Zyn 1. 56 3. 12 1. 56 0. 8 1. 56 Streptococcus faecalis gr D 5,434 P 1. 56 1. 56 1. 56 0. 8 1. 56 Streptococcus jaecalis gr D F 262 1. 56 1. 56 3. 12 1. 56 1. 56 Sarcina lutea ATCC 9,341. 6.35 6. 25 12. 5 Listeria monocytoyenes 5,844 11 0. 8 1. 56 0. 4 0. 4 1. 56 Listeria monocytogenes Ramtsse type IV 0. 8 1. 56 0. 4 0. 4 0. 4 Listeria monocytogencs Joubcrt E 102 0.8 1. 56 0. 4 0. 4 0. 8 Erysipelothrix insiaiose E 159 50. 05 0. 1 0, 2 50.05 0, 06 Erysi mum; insidiose A 21 3.12 3.12 0. 2 0.1 2o. 05 Bacil us cereus ATCC 10,702 0. 1 0. 1 0. 2 0. 05 20. 05 Bacillus cereus ATCC 9,634 $0.05 0. 2 0. 4 20. 05 0. 1 Bacillus subtilis Leugar A 156 0. 1 0. 1 0.1 Z0. 05 0. 05 Bacillus subtilis Scarle 0. 1 0. 1 0. 2 go. 05 zO. 05 Pasteurella septica type B 55,129 0. 2 o. s 1. so 1. so 30. 0s Pasteurella septica type 0 5,621 0. 8 0. 8 0. 1 $0. 05 0. 2 Pasteurclla pseudotuberculosis G 114 6. 25 6. 25 1. 56 1. 56 3. 12 Pasteurella joubert E 99 6. 25 6. 25 6. 25 3.12 6. 25 Escherichia coli A 223 IP 1. 56 1.56 1. 56 0. 8 0. 8 Escherichia coli Monod D 198... 0.8 1.56 1.56 0.8 1.56 Escherichia coli111 B4 A- 1. 56 1. 56 3.12 1. 56 3.12 Escherichia coli 26 B6 A.. 1. 56 1. 56 3.12 1. 56 3.12 Escherichia coli B5 A 1. 56 1. 56 3.12 1.56 3. 12 Escherichia coli ATCC 10,536- 1. 56 0. 8 1. 56 0.8 0.8 Klebsiella pneumoniae E 155.. 12. 5 1. 56 1. 56 12. 5 Aerobacter aerogenes E 115.. 0.8 0.8 12. 5 3. 12 3. 12 Citrobacter oi 1. 56 6. 25 3.12 1. 56 6. 25 Salmonella typhi O 001... 6. 25 6. 25 3.12 3. 12 6. 25 Salmonella para A A 220 IP 12. 5 25 6. 25 6. 25 3. 12 Salmonella para B A 214 IP 3. 12 3.12 1. 56 1. 56 3. 12 Salmonella pullorum yallinarum 465. 6. 25 25 3.12 1. 56 1. 56 Shigella dusenteriae 5,728 I? 1. 56 3. 12 1. 56 1. 56 3. 12 Shiyclla sonnei D 374 1. 56 3. 12 1. 56 0.8 0. 8 Morazella lwolfi D 50 50 50 50 50 Pseudomonas aeruginisa B 74. 50 50 50 50 50 Bordetella bronchiseptica 25 5 5 TABLE 1.ANTIBACTER1AL ACTION IN VlTRO-Continucd Staphylococcus loudonii 50. 05 0. 2 0. 2 50. 05 50, 05

Staphylococcus 209 IP 0. 4 0. 8 1. 56 0. 2 0. 2

Staphylococcus aureus Gervais D 319. 0.4 0.8 1.56 0.2 0.05

Staphylococcus aureus E 0. 2 0.8 0.08 $0.05 30. 05

Staphylococcus albus P 0 1,200 0.1 0. 2 0. 2 50. 05 0. 05

Streptococcus pyoyeucs gr A 561 11 1.56 6. 25 1. 56 0. 4 0. 2

Streptococcus pyoyenes gr A D 313. 0. 2 6. 25 0. 8 0. 4 50. 05

Streptococcus ayalactiae gr 13.. 1. 56 6. 25 1. 56 0. 4 0. 2

Streptococcus pyogenes gr 0... 4 6. 25 1. 56 0. 4 0. 2

Streptoooccusfaecalis var. Zymogenes.- 1. 56 12.6 .8 0.4 0. 2 Streptococcus faecalis gr D 5,434 11. 1. 56 3. 12 1. 56 0. 4 0. 2

Streptococcus faecalis gr D 1 2G 1. 56 12. 5 1.56 0. 2 0. 2 Sarcina lutea ATCC 9341 12.5 3.12 50 1.56 0.8 Listeria monocytoyenes 5,844 11 1. 56 1. 56 1. 56 0. 4 0. 2 Listeria monocyloyenes Ramisso type IV. 1. 50 0. 4 0. 2 0. 2 Listeria mouocytogenes J oubort E 102. 0. 4 1. 56 0. 4 0. 2 Erysipclothriz' insidiosa E 159 0.05 0. 2 0. 2 $0.05 Erysipelothrir insidiosa A 27. 3o. 05 o. 2 50. on 50. 05 Bacillus gereus A'ICC 10,702.. 0. 4 0. 4 0. 2 0 1 0, 05 Bacillus gerelts A'ICC 9,634... 0.4 0. 2 o. 2 0, 2 3'0, 05 Bacillus sub ilis Leugm' A 156 o. 4 3.12 0, a 0,1 50, 05 Bacillus subtilis Seam... 0. 4 0. 8 0. 2 50, 05 50, 05 Pasteurella sep ica typo B 50. 05 0. 8 0,1 50. 05 Pasteurella septica type 0 5,621... 0.4 50. 05 0.4 0, 4 Pasteurella pseudotuberculosis C 11 3.12 0.8 0.4 0, 4 Pasteurella joubert E 99 6. 25 0. 8 0. 4 0. 4 Escherichia coli A 223 IP... 0. 8 0. 8 0.4 0. 2 Escherichia coli Monod D 1 0.8 1.56 0.4 0,4 Escherichia coli111 B4 A 1.56 .8 0. 8 0.4

Escherichia coli 26 B6 A 1.56 56 0.4 0. 4 Escherichia coli'55 B5 A l. 56 0.8 0.8 0, 4 Escherichia coli A'ICC 10,536 0.8 1.56 0.4 0.4 Klebsiella pneumoniae E 12. 5 0.8 3. 12 1.56 Aerobacter aeroyenes E 115... 1. 56 2. 5 0.4 0. 4 Citrobacter oi 1.56 12.5 0.4 0.4

Salmonella typhi 0 001 6.25 1. 56 0.4 0.4 Salmonella para A A 220 IP 12. 5 3. 12 3,12 3, 12 Salmonella para B A 214 IP 6,25 1. 56 1.56 0. 4

Salmonella pullorum aallinarum 465........ 6.25 3. 12 0.4 0.4

Shigella dysenteriac 5,728 IP 3. l2 0. 4 0. 4 0. 4

Shigella sonnei D 374 3.12 0.8 0.4 0.2

Morazella lwofii D 50 50 25 50 Pseudomonas aeruginisa B 74 50 50 50 50 Bordetella bronchiseptica 50 25 50 TABLE l.-ANTIBACTERIAL ACTION IN VITRO-Continued 0 5-D 8 8 65 0 5 MMMMMM MMm m0 0 M00 00 0 0 0 0 3 0 00 0L LL L LLfiLx -Cominued I 1 30031101 umnnmm numwmmwmxwx 3LL1 1 33 333330333033LL ANTIBACTERIAL ACTION IN VITRO TABLE 1.-

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2. The compound of claim 1 having the formula
 3. The compound of claim 1 having the formula
 4. The compound of claim 1 having the formula 